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Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer

  • Matthew D Galsky 1,
  • Amir Mortazavi 2,
  • Matthew I Milowsky 3,
  • Saby George 4,
  • Sumati Gupta 5,
  • Mark T Fleming 6,
  • Long H Dang 7,
  • Daniel M Geynisman 8,
  • Radhika Walling 9,
  • Robert S Alter 10,
  • Mohamad Kassar 11,
  • Jue Wang 12,
  • Shilpa Gupta 13,
  • Nancy Davis 14,
  • Joel Picus 15,
  • George Philips 16,
  • David I Quinn 17,
  • G Kenneth Haines 3rd 18,
  • Noah M Hahn 19,
  • Qianqian Zhao 20,
  • Menggang Yu 20,
  • Sumanta K Pal 21
1 Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA 2 Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, and the Comprehensive Cancer Center, Columbus, OH, USA 3 Division of Hematology and Medical Oncology, University of North Carolina School of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA 4 Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA 5 Division of Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA 6 US Oncology Research, Virginia Oncology Associates, Hampton, VA, USA 7 Ochsner Medical Center, Baton Rouge, LA, USA 8 Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA 9 Community Regional Cancer Care, Community Health Network, Indianapolis, IN, USA 10 John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA 11 Community Hospital, Munster, IN, USA 12 University of Arizona Cancer Center at Dignity Health St Joseph's Hospital and Medical Center, Phoenix, AZ, USA 13 Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA 14 Division of Hematology and Medical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA 15 Division of Oncology, Department of Medicine, and Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA 16 Division of Hematology and Medical Oncology, Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC, USA 17 Division of Oncology, University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA, USA 18 Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 19 Department of Oncology and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 20 Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA 21 Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA

Publication: Journal of Clinical Oncology, June 2020

DOI: 10.1200/JCO.19.03091

Purpose 

Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. “Switch maintenance” therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons.

Patients and methods 

Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS).

Results 

Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival.

Conclusion 

Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

Commented by Dr. Francesco Soria

In this randomized double-blind phase II trial patients with metastatic urothelial carcinoma (mUC) achieving at least stable disease after first-line platinum-based chemotherapy were randomized to receive either pembrolizumab 200 mg up to 24 months or placebo. Interestingly, patients with disease progression on placebo could cross over pembrolizumab. The primary endpoint of the study was progression-free survival (PFS). Overall, 108 patients were randomly assigned to pembrolizumab (n=55) or placebo (n=53) between 2015 and 2018. PFS was significantly longer in the treatment group (5.4 months vs 3 months, p=0.04). Moreover, median overall survival was 22 months for pembrolizumab and 18.7 months for placebo. Based on these results, switch to pembrolizumab after-first line platinum-based chemotherapy could become the new standard of treatment for mUC patients.

The advent of systemic immunotherapy revolutionized the paradigm of treatment of advanced and mUC. To date, five PD-1/PD-L1 inhibitors have been approved for the treatment of mUC patients who have progressed or were ineligible for platinum-based chemotherapy. Actually, platinum-based chemotherapy remains the first-line standard treatment for mUC and is usually administered for 6 cycles and then discontinued. Unfortunately, the oncologic outcomes after this therapy are mainly unsatisfactory, with reported median PFS of around 3 months. Therefore, alternative or complementary new effective treatments are urgently needed.

In this trial, Galsky et al. tested the efficacy of pembrolizumab following platinum-based chemotherapy in patients achieving at least a stable disease after first-line treatment. As the authors commented, the idea is very attractive since chemotherapy may induce immunogenic cell death and/or depletion of suppressive immune cell populations, thereby enhancing the activity of subsequent immunotherapy. Moreover, there is evidence that metastases driven mutations are associated with drug resistance rather than tumorigenesis, thus reinforcing the rationale for maintenance therapy.

Finally, the potentially game-changing value of this trial has been corroborated from the results of the Javelin Bladder-100 trial, recently presented at ASCO 2020. In this phase III study, switch to avelumab (PD-L1 inhibitor) after first-line chemotherapy significantly prolonged overall survival compared to best supportive care. Taken together, these trials will probably lead to a next change in clinical practice, thus broadening the range instruments in the hands of the uro-oncologists.